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Alzheimer's, Memory, and Acetylcholine

I Alzheimer's.

Alzheimer's disease was first discovered in 1906 by Alois Alzheimer. Alzheimer's disease is a progressive, degenerative, and irreversible neurological disease with no cure. Alzheimer's disease affects an estimated four million American adults, which is approximately one in ever three families.

Brain tissue shows "neurofibrillary tangles" (twisted fragments of protein within nerve cells that clog up the cell), "neuritic plaques" (abnormal clusters of dead and dying nerve cells, other brain cells, and protein), and "senile plaques" (areas where products of dying nerve cells have accumulated around protein). Although these changes occur to some extent in all brains with age, there are many more of them in the brains of people with AD.

The destruction of nerve cells (neurons) leads to a decrease in neurotransmitters (substances secreted by a neuron to send a message to another neuron). The correct balance of neurotransmitters is critical to the brain. Three neurotransmitters commonly affected by AD are acetylcholine, serotonin, and norepinephrine. With acetylcholine being the most affected.

By causing both structural and chemical problems in the brain, AD appears to disconnect areas of the brain that normally work together.

As many as 4 million Americans currently suffer from AD. The most important risk factors for dementia are old age and a family history of dementia. The older you get, the greater your risk of developing AD.

About 10 percent of all people over 70 have significant memory problems and about half of those are due to AD. The number of people with AD doubles each decade past age 70. Having a close blood relative who developed AD increases the risk of getting this disease. Because women usually live longer than men, they are more likely to develop AD.

There are two types of AD -- early onset and late onset. In early onset AD, symptoms first appear before age 60. Some early onset disease runs in families and involves autosomal dominant, inherited mutations that may be the cause of the disease. So far, three early onset genes have been identified. Early onset AD is less common, resulting in about 5-10% of cases.

Late onset AD, the most common form of the disease, develops in people 60 and older and is thought to be less likely to occur in families. Late onset AD may run in some families, but the role of genes is less direct and definitive. These genes may not cause the problem itself, but simply increase the likelihood of formation of plaques and tangles or other AD-related pathologies in the brain.

Alzheimer's can and does occur within familial clustering. Some families with pre-senile dementia have shown three different genes which are associated with Alzheimer's pathological features. These genes carry on several mutations which have an autosomal dominant transmission, each mutation seems to be able to cause pathological changes.

The actual onset of Alzheimer's disease is unclear, but symptoms can appear as early as age 40 but more frequently around the age of 65. Approximately half of men and women over the age of 85 have Alzheimer's disease. The youngest documented case was that of a 28-year-old. More women are affected with Alzheimer's disease then men and nearly 100,000 people die of complications from Alzheimer's annually, making it the forth largest killer of adults in the United States.

The etiology of Alzheimer's disease is heterogeneous but does have common clinical and pathological features. These pathological features may include impaired memory, impaired thinking, impaired behavior, and difficulty in grasping or in expressing thoughts. The loss of memory, by making it difficult to perform familiar tasks, has an adverse influence on work skills, social skills, and everyday house keeping skills. These tasks may include the preparation of meals, the learning of new tasks, holding down a job, family life, or problems with language. With a gradual onset, persons with Alzheimer's disease are usually aware of their problems and often say their thoughts are jumbled. As Alzheimer's disease progresses a person may experience decreased judgment, disorientation, impairment in abstract thinking, changes in mood, abnormal behavior, and personality changes.

The cost of Alzheimer's is high, not only in human suffering but also in economics. Over ninety billion dollars alone is spent annually for care of patients with Alzheimer's disease in the United States.

II Neuropathology of Alzheimer's and Memory.

The most striking symptom of the dementia associated with Alzheimer, is the loss of memory. This memory loss is due to decline in neurons in the cortex.

The following below shows a healthy normally aged neuron on top and one in the later stages of Alzheimer's disease on the bottom.

Alzheimer's disease presents itself with either an early-onset or senile dementia. Senile plaque is clusters of dead or dying neurons mixed together with fragments of protein molecules. As Alzheimer's disease runs its course there are many changes at the cellular level. The degeneration neurons form senile plaques and neuro-fibrillary tangles.

The following image from Harvard Medicine shows a healthy, normally aged brain on the left and, on the right, one in the later stages of degeneration from Alzheimer's disease. Extensive spaces in the fissures and sulci of the brain reflects the loss of brain tissue caused by dead and dying neurons.

The only sure way to confirm a diagnosis of Alzheimer's disease remains to examine brain tissue under a microscope, which is usually done upon an autopsy.

III Memory and Acetylcholine.

Acetylcholine (ACh) was discovered in the 1920s, making Acetylcholine (ACh) the first known neurotransmitter. This neurotransmitter can be found in the brain, neuromuscular junctions, spinal cord, and in both the postganglionic terminal buttons of the parasympathetic division of the autonomic nervous system and the ganglia of the autonomic nervous system.

Only recently it was discovered that the nucleus basalis, particularly in the nucleus basalis of Meynert, is a source of acetylcholine (ACh). It was subsequently shown that projections from the nucleus basalis provide the primary source of neocortical acetylcholine (Mesulam and Van Hoesen, 1976; Lehmann, Nagy, Atmadja, & Fibiger, 1980). There are also cholinergic projections from the adjacent medial septum and diagonal band of Broca to hippocampus (Squire, 1987). All these cholinergic projections together making up a wide source of acetylcholine (ACh) in the brain.

Acetylcholine (ACh) role in learning and memory is on clear but Deutsch in 1970 believed that because most the acetylcholine (ACh) in the neocortex originates in the basal forebrain, that cholinergic synapses themselves were the sites for memory storage. However Squire believes these cholinergic pathways are better suited for some type of modulator role but in what way is yet unclear. The ascending, widely projecting cholinergic pathways seem better suited as a modulator system than as an information-containing, information-storing system (Squire, 1987).

IV Acetylcholine and Memory Defect in Alzheimer's.

One of the characteristic changes that occurs in Alzheimer's disease is the loss of memory and the loss of acetylcholinesterase (AChE) from both cholinergic and noncholinergic neurons of the brain. However, AChE activity is increased around amyloid plaques. (Sberna, Saez-Valero, Beyreuther, Masters, and Small, 1997) This increase in AChE may be of significance for therapeutic strategies using AChE inhibitors.

Amyloid beta-protein (A beta), the major component of amyloid plaques, acts on the expression of AChE. A beta peptides spanning residues 1-40 or 25-35 increased AChE activity in P19 embryonal carcinoma cells. A peptide containing a scrambled A beta (25-35) sequence did not stimulate AChE expression. Way then an increase in AChE, the increase in AChE expression around amyloid plaques could be due to a disturbance in calcium homeostasis involving the opening of L-type VDCCs. (Sberna, Saez-Valero, Beyreuther, Masters, Small, 1997)

The deposit of these beta-amyloid peptides in the brain in form of senile plaque is the key event responsible for Alzheimer pathology. Among various mechanisms that have been proposed to explain the Neuro toxicity of beta-amyloid deposits, beta-amyloid peptides may be indirectly toxic for neurons by activating micro glial cells to produce NO (2). (Bianchini, 1996)

The degeneration of the cortex, basal forebrain, and hippocampus, in this way leads to a profound loss of memory.

Acetylcholine receptors are neurotransmitter receptors. Neurotransmitter receptors are proteins that react with extracellular signals, such as acetylcholine, and convert them into intracellular effects (Hucho 1993). They are integral membrane proteins, that is they are within the cell membrane as shown in the figure. ACh receptors are ligand gated ion channels, and they are found on the post synaptic membrane on the target cells.

ACh receptors are one of the chief receptors for excitator neurotransmitters (Alberts et al. 1998). A signal to move a muscle travels from the CNS down a motor neuron to the target muscle cell (www.macalester.edu). The binding of acetylcholine to ACh receptors results in a change in memprane potential of the target cell leading to an action potential in the muscle cell. The acetylcholine is rapidly removed by enzymatic breakdown or reuptake so that when the presynaptic cell stops, the post synaptic cell will stop as well. When the neurotransmitter binds with the receptor, the channel opens and allows Sodium ions into the cell which depolarizes the plasma membrane to create the action potential (Alberts et al. 1998). There are two subtypes of acetlycholine receptors. A predominantly excitatory one in the PNS and another in the autonomic ganglia and CNS. They are typically called muscular and neuronal. There are several subtypes of AChR but the one specified here is the nicotinic AChR. It has two binding sites, and has elaborate pharmacology and toxicology. Because of this, it has been identified, characterized and isolated.

V Treatment of Alzheimer's.

There is no known cure for Alzheimer's disease, however numerous medications are undergoing testing for the treatment of the dementia associated with Alzheimer's. Many of these treatments seek to replace the depleted levels of acetylcholine (ACh) in the Alzheimer's patients brain. Autopsy studies of patients with Alzheimer's disease revealed lesions in the cholinergic neurons of the nucleus basalis. (Whitehouse, Price, Struble, Clark, Coyle, & Delong, 1982).

Drugs undergoing testing in the United States include tetrahydroaminoacridine (THA, Cognex) and L-acetyl carnitine (Alcar). Cognex is the first drug to be approved by the FDA for treatment of Alzheimer's. Both drugs work on enhancing the brains cholinergic system.

Medical Treatment of Alzheimer's

There is no known cure for Alzheimer's disease, however numerous medications are undergoing testing for the treatment of the dementia associated with Alzheimer's. Many of these treatments seek to replace the depleted levels of acetylcholine (ACh) in the Alzheimer's patient brain. Autopsy studies of patients with Alzheimer's disease revealed lesions in the cholinergic neurons of the nucleus basalis. (Whitehouse, Price, Struble, Clark, Coyle, & Delong, 1982). Drugs undergoing testing in the United States include tetrahydroaminoacridine (THA) and L-acetyl carnitine (Alcar). Both drugs work on enhancing the brains cholinergic system.

VI Treatment Results

With no cure it sight for Alzheimer's disease, the best that can be hoped for is to lessen the symptoms. There are medications that can lessen agitation, anxiety, unpredictable behavior, improve sleeping patterns, and treat depression. (Snyder, 1996)

Tetrahydroaminoacridine (THA, Cognex) produces a modest improvement in symptoms in most patients but does not slow down the disease itself. Cognex, while having a quite modest improvement on memory, language, and other cognitive functions, has a dramatic effect on the behavior of a person with Alzheimer's disease. (Yudofsky, Hales, and Ferguson, 1992) Symptoms of the Alzheimer's disease, including apathy, irritability, and agitated behavior, are significantly decreased by Cognex therapy.

There is however a price to pay for this modest improvement. In about half of all persons who take Cognex, there is a rise in liver enzymes which usually occurs after about 4 to 6 weeks into Cognex therapy. (Opler, 1996)

There is a new drug soon to be released that does look promising, NDA (New Drug Application) for donepezil (Aricept, E2020) was filed in April. Based on the pre-release data, this drug should do for the treatment of Alzheimer's disease what Prozac did for treating depression.

Although Alzheimer's disease is currently incurable, it can be treated with medications to slow down the progression. Many of the medications that have been developed act to increase the amount of acetylcholine in the brain. Acetylcholine is the chemical messenger that sends messages from one neuron (brain cell) to another in the area of the brain used for memory. Other medications being tested for the prevention and treatment of Alzheimer's disease include anti-inflammatory drugs, estrogen, antioxidants, and medications that treat blood vessel risk factors, such as high blood pressure and high cholesterol. Behavioral programs are also an important part of any treatment plan for the person with Alzheimer's disease.

Levels of acetylcholine, the main chemical messenger in the brain, are lowered in Alzheimer's disease. Medications that serve to increase its levels by inhibiting a substance called cholinesterase can improve behavior and thinking in patients with Alzheimer's disease. Medications in this category have similar efficacy and include: Tacrine was the first drug in this class to be approved for use, but it is now rarely used due to excessive side effects.

Donepezil has similar benefits to tacrine, but it is much less toxic to the liver. It is given only once a day, and it may be slightly more effective than tacrine.

Rivastigmine is a twice-a-day medication that was approved in 2000 for the treatment of mild to moderate symptoms of Alzheimer's disease. In preliminary trials, rivastigmine was associated with greater improvement in performance tests than any other drug in its class.

Galantamine (also called galanthamine) was approved in 2001 by the Food and Drug Administration after a number of studies showed that it offered benefit to persons with Alzheimer's disease. Galantamine is available in either once-a-day or twice-a-day doses.

Memantine was approved in the United States in October 2003 to treat moderate to severe Alzheimer's disease after studies showed that it delayed progression of the disease. Memantine has been widely used in Europe to treat dementia. It helps regulate glutamate, an important chemical messenger in the brain. Memantine can help Alzheimer's patients slightly improve their ability to perform daily activities and slow their rate of cognitive decline. It has not been shown to have a significant effect on mild Alzheimer's disease.

Vitamin E has been touted as a possible preventive or progression-slowing treatment for Alzheimer's disease because of its antioxidant effects. Antioxidants are substances that combat the effects of oxidative damage in our bodies. Oxidative damage to proteins and DNA occurs when our cells utilize oxygen to produce energy. Toxic byproducts of that process are called reactive oxygen species, a kind of free radical. Natural substances in the body (antioxidants) act to scavenge these dangerous molecules and render them less harmful, but this protection fails over time. Oxidative damage has been implicated as a possible cause or contributor to the damage in Alzheimer's disease.

Studies of vitamin E's effects on Alzheimer's disease have been mixed, with some showing a benefit and others showing no significant effect. Because vitamin E can have side effects, such as bleeding in people who take blood-thinning medications like warfarin, you should discuss vitamin E supplementation with your doctor. Also, vitamin E may interfere with the effects of some cholesterol-lowering medications.

Gingko biloba is an herb that may increase blood flow to the brain. Some studies have suggested benefit in Alzheimer's disease, but these studies were conducted in Europe, where the content and dosage of herbal supplements is much more consistently regulated than in the United States. Gingko biloba can also increase the risk of bleeding and should not be taken without first checking with your doctor.

Simple steps can be taken that can reduce the confusion felt by persons with Alzheimer's disease and decrease the agitation that such confusion can produce. Large calendars and digital clocks and familiar objects in a simple, uncluttered environment are useful. Setting up a daily routine and using written reminders can help the person with Alzheimer's stay more active. Exercise, occupational therapy, group therapy, music and family activities are often helpful too.

As the disease progresses, the person with Alzheimer's disease can become progressively more agitated. Simple distractions, touching and talking can often calm them. When persons with Alzheimer's disease have difficulty keeping facts straight (such as wanting to go visit a deceased parent), caregivers are encouraged to redirect and empathize with the person instead of correcting them. Home movies and videos can be soothing as well.

In later stages of the disease, the caregivers must assume full responsibility for all aspects of daily living. Alzheimer's patients need help with dressing, bathing and eating. They must be prevented from driving. As the disease progresses, wandering can become a serious problem. Door locks and alarms may be needed; identification bracelets, such as those issued by the Alzheimer's Association are recommended.

How quickly someone progresses to the late stages of Alzheimer's disease varies from person to person. In the later stages of the disease, Alzheimer's patients may become totally incontinent (cannot control their urine or bowels). They may become bedridden, with the risk of pressure sores and pain from muscle contractures. They may lose the ability to swallow and may not be able to eat or drink. Though many spouses and children strive for years to keep their loved ones with Alzheimer's disease at home, most patients come to require around the clock nursing care. Families must make critical decisions about end of life care (feeding tubes, respirator use, antibiotic use, and hospitalization). Many families choose to have the medical care of their loved one with late-stage Alzheimer's disease focus more on maintaining comfort, dignity, and quality of life rather than performing tests and undergoing treatments. Ideally, the patient, the family and the physician have come to these decisions well in advance and are all in agreement.

Caregivers and family members of persons with Alzheimer's can be devastated by the slow deterioration and loss of their loved ones. No one can provide care for a person with Alzheimer's without help. Doctors, nurses, hospital social service departments, local elderly service administrations, local support groups and the Internet can provide referrals for assistance to caregivers.

References

Deutsch J. A. (1971) The cholinergic synapse and the site of memory. Science 174: 788-794.

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